Circulating β cell-specific CD8 + T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Clin Exp Immunol. 2020 Mar;199(3):263-277. doi: 10.1111/cei.13391. Epub 2019 Nov 10.

Abstract

In type 1 diabetes (T1D), autoreactive cytotoxic CD8+ T cells are implicated in the destruction of insulin-producing β cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8+ T cells that recognize peptides presented by these class I molecules on pancreatic β cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8+ T cells in HLA-B*3906+ children newly diagnosed with T1D and in high-risk HLA-A*2402+ children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8+ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906+ children with T1D, we observed an increase in PPI5-12 -specific transitional memory CD8+ T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI5-12 -specific CD8+ T cells in HLA-B*3906+ children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8+ T cells. In longitudinal samples from high-risk HLA-A*2402+ children, the percentage of terminal effector cells within the InsB15-24 -specific CD8+ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8+ T cells in T1D. Collectively, our results provide evidence that β cell-reactive CD8+ T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.

Keywords: HLA-A*24; HLA-B*39; CD8+ T cells; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • HLA-A24 Antigen / immunology
  • HLA-A24 Antigen / metabolism
  • HLA-B Antigens / immunology
  • HLA-B Antigens / metabolism
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Infant
  • Insulin / immunology
  • Insulin / metabolism
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Protein Precursors / immunology
  • Protein Precursors / metabolism
  • Risk Factors

Substances

  • HLA-A*24:02 antigen
  • HLA-A24 Antigen
  • HLA-B Antigens
  • Histocompatibility Antigens Class I
  • Insulin
  • Protein Precursors
  • preproinsulin